The discovery of novel pharmacological interventions to increase the probability of successful cocaine abstinence has been tedious since chronic cocaine use has not historically been assumed to produce prolonged physiological withdrawal symptoms upon discontinuation. However, since some individuals can remain casual recreational users of the drug, there may be factors in addition to cocaine's reinforcing properties that determine why other individuals progress to compulsive drug use. A better understanding of potential environmental events that can alter drug intake will increase knowledge of the etiology of drug addiction and may result in the more effective and efficient treatment of compulsive cocaine use and withdrawal. Differences in the amount, severity or sensitivity to environmental stress or anxiety may be one factor which predisposes some individuals to engage in compulsive drug use. During the initial period of funding for this project, a behavioral paradigm was successfully developed which demonstrated that exposure to uncontrollable footshock stress increases vulnerability to self-administer cocaine in rats. The experiments described in this application were designed to focus on the interactions between pharmacological interventions, environmental stress, stress hormones and cocaine self-administration. Acute and chronic treatment regimens with benzodiazepine anxlolytics (e.g., chlordiazepoxide, alprazolam), non-benzodiazepines (e.g., buspirone, trazodone) as well as drugs which affect plasma corticosterone and ACTH (e.g., metyrapone) or bind to adrenocorticosteroid receptors (e.g., aldosterone, spironolactone, mifepristone) will be investigated before and following the acquisition of cocaine self-administration to determine if these drugs reverse the effects of stress or stress hormones (e.g.. corticosterone, ACTH) on the initiation of this behavior and/or attenuate drug-intake once this behavior has been established. In addition, the neurobiological mechanisms potentially involved in the mediation of these processes will also be investigated using quantitative receptor autoradiography and in vivo microdialysis. The results of these investigations will increase knowledge of behavioral, neurobiological and neuroendocrine variables that potentially contribute to cocaine self-administration in rats and may, therefore, assist in the development of novel pharmacotherapies for the treatment of cocaine withdrawal and abstinence in humans.